Gordon Stein, CFO of CleanTech Lithium, explains why CTL acquired the 23 Laguna Verde licenses. Watch the video here.
Touk, given the following thresholds for the various mechanisms of action of dox:
DNA adduct formation 25nM
Free radical formation/cardiomyocyte apoptosis1 100nM
Topoisomerase Inhibition1 400nM
And that DNA adduct formation is the mechanism of action that provides the greatest effect in reducing the tumour size, and that the range discovered in tumours was 76-2310, it suggests there is sufficient dox getting into the tumour, and all but 2 of the biopsies exceeded all the threshold above.
Now it would be good to have a chart which demonstrated the efficacy of dox (at least in average terms) against values from these thresholds and above. This would really put the argument to bed. I have had a scour around but cannot actually find any relevant data - as AS himself stated was the case a while back.
Clearly: more ava6000, more cleavage, more dox, more cancer cells disrupted
I’m sure: if any competent scientist were performing a trial, they would ensure that the data collected would inform them on the effects of increased dosing. Such as the half life of the dose. They wont be making decisions in a vacuum.
Not trying to win any arguments here, just trying to make logical sense of it all.
Clearly increasing dose frequency will increase the efficacy, and they can keep on increasing the frequency beyond 2 weeks exactly because it has been shown to be safe. I'm sure they have already calculated and identified that 2 weeks will deliver the results they're after. Once approved, all other combinations can be tried out by clinicians as they build up their knowledge of this drug.
As for the backers... we had first hand evidence that there are plenty who backed the raise with absolutely no clue of the underlying science.
I'd say most of it is excreted, given the half life of ava6000, but that's not the important bit here, it's actually how much is converted and concentrated in the tumour, and the answer from the biopsies is there is enough to be therapeutic. The excretion of the majority of it is a necessary part of the process. If you consider that in order to get a sufficient concentration to the tumour through the bloodstream, it is a requirement to raise the levels of AVA6000 throughout the body. Only the AVA6000 that happens to pass by the tumour will be cleaved. The excreted AVA6000 represents all the dox that would otherwise be absorbed by healthy tissue, so it's an overwhelmingly positive thing.
Roll on the half life extending serum they're working on and one can only imagine the boost to efficacy.
Careful what you wish for indeed. HE1 replaced their CEO and the new one (Lorna) duly sold every single existing shareholder down the river to the tune of a 95% dilution. Effectively gave the company away to the spivs.
I'm more supportive of retaining AS but surrounding him with the right experience for this phase of the venture.
They were taken 24h after the dose of ava6000 was administered - see here: https://avacta.com/wp-content/uploads/2023/02/MASTER-DECK-Avacta-Science-Day-23.02.23_compressed-1.pdf
I suspect that any dox cleaved by fap will be absorbed in the same way as straight dox and so will have a half life of 20-48h before being excreted, although it's not stated whether this applies to tumour tissue as well.
I can see a dosing regimen where dox to the tumour is topped up frequently so as to counter this half life excretion and maintain the assault on the tumour cell division, as working well. I'm sure that Avacta scientists and the clinicians involved are all itching to try these various approaches and it's just the reality of business, time, resources etc. which are limiting this to 2 weeks, with the focus remaining on getting this through and approved.
Thorn, the mouse models, biopsies etc. have all show us that the mechanism is working, so this means doxorubicin is getting deposited in the tumour and in sufficient concentrations to start killing tumour cells. The did provide us with the values in the science day. So this much we do know.
The independently defined therapeutic thresholds for the various mechanisms of action were listed in the science day slides as:
Doxorubicin Target Activity DOX IC50
DNA adduct formation 1 25nM
Free radical formation/cardiomyocyte apoptosis1 100nM
Topoisomerase Inhibition1 400nM
In vitro cytotoxicity2 30nM-3µM
Whereas, biopsies were in the range 79-2419nM.
This doesn't tell us what the values would be for straight dox, I agree.
It is true to say that straight dox is sucked up into the cells rapidly, with an initial half life of 5 minutes from tissue absorption alone. Once inside the cells they do their damage, both to the tumour cells, and to healthy tissue around the body. Essentially it is cells currently undergoing division are targeted by the dox (this is the most significant mechansim). Once inside the tissue there is a longer terminal half-life of 20-48 hours.
So it's probably safe to say on a like for like dose more straight dox will reach the tumour in the concentrations in which it is administered. However, you are also killing the person at the same time, which is less than ideal. You are also restricted to 3 weekly dosing due to the damage caused by the non-targeted distrubution of dox around all tissues.
Now considering the mechanism of action whereby only dividing tumour cells are actually destroyed by dox, and that only a subset of cells are dividing at any given time, the efficacy of administering straight dox (all other pharmacokinetic considerations aside) is limited by:
1. the number of dividing cells that can be targeted before dox is fully excreted
2. the growth of the tumour between the time the concentration of dox has dropped below an efficacious dose and the next dose can be administered
3. the time that has to be elapsed before a patient can receive another dose
Clearly if 2 is greater than 1, then sadly the tumour continues to grow (albeit more slowly) and the patient is very very sick from the doxorubicin alone.
Now compare the above to precision. Given that no mtd has been found yet, clinicians are free to adjust:
a. elapsed time between dosing
b. duration of a single dose ie. the rate it is administered
c. the maximum concentration of a single dose
all in the knowledge that healthy tissues are spared. Given we know there is already a therapeutic concentration found in biopsies, it is clear in my mind that if the dosing frequency and concentration are optimal, the clinicians will be able to ensure that dox can be administered to the tumour at such a rate that 1. (above) is greater than 2. and so the tumour begins to shrink.
This is all premised on the tumours being high fap and having
It's looking like the SP is struggling to get back above the support line that Zak Mir pointed out. Would it be sensible wyndrum, to take a bit off the table, just to hedge against the possibility of a 10-15% drop from here that you have suggested?
So let's get this straight please wyndrum and aldebaran, is the share price going to rise from here? Does this mean we're well and truly out of the death spiral scenario, and Alan Smith is competent once again. I was under the impression that we need to dislodge him. How does this work - last week we needed to get him ousted with pitch forks?
Thorn - help me out here?
95% of all gaps are filled, plus remember the convertible bond death spiral that Thornogson kept going on about, that will definitely drag us down to 20p.
Isn't that right Thorn?
Over the coming months there's going to be massive dilution and it will provide downward pressure all the way down to 20p, maybe beyond?
The mechanisms employed, namely the conversion bond and raising exclusively with II’s at a huge discount (bar throwing a bone to long termers) supports that argument that they are reshaping the register. However, I don’t necessarily buy this given some of the “diamond handed” II’s that we saw participated. In addition, we’ve not seen a single tr1.
Nevertheless, this is still bargain territory and whatever the ultimate reasons for the raise, buying down here is still better than buying up at 160 by a factor of 4.